The long-term objective of this project is to understand the genetic mechanism(s) underlying the natural resistance to hemopoietic allografts. As an initial approach towards the stated objective, three specific aims are proposed: 1) to determine the location of the Hh-1 locus in the H-2-b and H-2-d chromosomes by determining restriction fragment length polymorphism (RFLP) in a panel of H-2S/D recombinant haplotypes, 2) to identify and isolate the Hh-1 genes, using human and murine probes for the H-2S/D interval and H-2-b and H-2-d cosmid libraries, and 3) to initiate the characterization of the genes thus identified. The proposed approach should provide new insight into the genetic mechanism underlying natural resistance and the recognition function of NK cells. In addition, these studies should help identify homologous genes in man, improve the prospect of clinical bone marrow transplantation, and possibly develop NK cell-mediated cancer immunotherapy.